α-hydroxy-β-aminocarboxylic acid and amide derivatives are found in a variety of natural products and pharmaceutically active substances.
Subunits incorporating the α-hydroxy-β-aminocarboxylic acid motif have been termed “norstatine” derivatives, and serve as key intermediates for the synthesis of the general class of P1-α-ketocarboxylic transition-state inhibitors of serine or cysteine proteases. Such inhibitors are finding increasing applications in medicine for the treatment of a diverse array of disease states including thrombosis, cancer, and osteoporosis.
Towards this end, α-hydroxy-β-aminocarboxylic acid, ester and amide derivatives serve an important role as the most common precursors for the preparation of these α-hydroxy-β-aminocarboxylic acid-incorporating drug candidates.
Electrophilic α-dicarbonyl compounds are regarded as interesting and highly reactive functional arrays which are capable of undergoing a myriad of transformations.
Such chemical properties can be exploited in novel and therapeutically useful ways by strategically incorporating these reactive α-ketocarboxylic moieties into a peptidic or peptidomimetic matrix.
Multicomponent reactions (MCRs) such as the Passerini and Ugi reactions offer the ability to rapidly and efficiently generate collections of structurally and functionally diverse organic compounds. The Passerini reaction is a chemical reaction involving isocyanides, aldehydes or ketones, and carboxylic acids to form α-acyloxy amides. Compounds that are available through the Passerini reaction may form highly valuable building blocks in the convergent synthesis of compounds with medicinal effects, such as for instance the prolyl dipeptide inhibitors Telaprevir or Boceprevir.
WO2007/0022450 discloses for instance the preparation of a cyclopropylamide by the coupling of Cb-norvalinal with cyclopropyl isocyanide in the presence of trifluoroacetic acid. The obtained compound is then deprotected, and the aminoalcohol then employed in a synthesis of Telaprevir. However, the disclosed synthesis is cumbersome, and only allows for a limited yield and variation of the building blocks involved.
Accordingly, the access to such compound through a more selective and higher yielding route would be highly desirable.